EP0700682A2 - Medicament containing prothrombin for antagonizing blood-anticoagulents - Google Patents
Medicament containing prothrombin for antagonizing blood-anticoagulents Download PDFInfo
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- EP0700682A2 EP0700682A2 EP95112569A EP95112569A EP0700682A2 EP 0700682 A2 EP0700682 A2 EP 0700682A2 EP 95112569 A EP95112569 A EP 95112569A EP 95112569 A EP95112569 A EP 95112569A EP 0700682 A2 EP0700682 A2 EP 0700682A2
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- prothrombin
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- antagonizing
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- anticoagulants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4833—Thrombin (3.4.21.5)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Definitions
- the invention relates to an antidote for blood anticoagulants.
- Blood clotting is a complex process involving plasma proteins and cells.
- the formation of a wound closure is initiated by the rapid adhesion of platelets to the damaged surfaces and by proteases and contact factors, which are activated in succession in a cascade-like reaction sequence.
- proteases and contact factors which are activated in succession in a cascade-like reaction sequence.
- thrombin which among other things catalyzes the activation of fibrinogen to fibrin.
- Proteins such as factors VIII and V contribute to the efficiency of this system.
- inhibitors of the proteases involved essentially regulate the coagulation processes in such a way that wound closure occurs, but excessive reactions are avoided. If this fine-tuned balance is disturbed, fibrin deposits or the formation of thromboses can result.
- resulting vascular occlusions are the cause of many pathophysiological processes, such as heart attacks in particular. This problem is particularly important in those patients who are at increased risk of thrombosis, which is often a postoperative complication.
- thrombolysis In order to prevent thrombus formation or to support its dissolution (thrombolysis), anticoagulants are often used in the clinic, which affect the coagulation process in different ways intervention.
- anticoagulants In addition to the reduction or prevention of platelet functions (aggregation, adhesion, activation, synthesis and release of activation products), inhibitors of coagulation proteases involved, in particular the thromboplastin / factor VIIa complex, factor Xa and in particular thrombin (factor IIa) are examined and applied .
- hirudin A particularly specific and potent inhibitor of thrombin is hirudin, which was originally isolated from the salivary glands of the leech Hirudo medicinalis.
- hirudin A particularly specific and potent inhibitor of thrombin is hirudin, which was originally isolated from the salivary glands of the leech Hirudo medicinalis.
- Various variants, analogs, fragments and mutants thereof are now known and are being examined for their suitability.
- the hirudin In its naturally occurring form, the hirudin is sulfated, but it has been found that the interesting biological activity is retained even in the non-sulfated form.
- the hirudin or the hirudin derivatives can therefore be conveniently produced using the means of genetic engineering.
- Blood anticoagulants also include heparin, its fragments and variants, and synthetic inhibitors that inhibit the catalytic activity of thrombin and other coagulation proteases, such as factor Xa. These components can also be used in the prophylaxis and / or therapy of thrombotic or prethrombotic complications.
- the search for more specific and potent anticoagulants or antithrombotics reflects the unsatisfactory situation that the clinically established substances such as heparins or vitamin K antagonists are either not effective enough or that they have undesirable and sometimes serious side effects.
- Hirudin is the strongest thrombin inhibitor currently known and does not interfere with the other enzymes in the blood coagulation cascade. So far, no significant side effects on the heart rate, respiration, blood pressure, the number of platelets, the fibrinogen or hemoglobin content have been observed. Therefore, hirudin is a preferred blood anticoagulant.
- anticoagulants or antithrombotics on the patient naturally entails the risk of an increased tendency to bleed, which occurs in extreme situations, e.g. improper use or dosage can lead to uncontrolled bleeding.
- improper use or dosage can lead to uncontrolled bleeding.
- an antidote also known as an antidote, must be made available.
- thrombins and their blocked variants show a certain hirudin-neutralizing effect, but on the one hand the use of active thrombin in patients who are treated with blood anticoagulants is usually contraindicated and on the other hand the preparation of inactive thrombin by application Low molecular weight, covalent bonds inhibitors due to the toxicity of these substances problematic. There is also no experience as to whether these complexes may have an antigenic effect. Because of their nature, these complexes are not suitable for neutralizing low-molecular (synthetic) antithrombines or antithrombotics. Meizothrombin, an intermediate product that arises during activation from prothrombin to thrombin, has a certain potency to antagonize, but it can quickly convert to thrombin in vivo and as such is usually contraindicated.
- anticoagulant or antithrombotic substances include glycosaminoglycans and sulfated polysaccharides, including heparins, in particular unfractionated and low molecular weight (LMW) pentosan polysulfate, heparan sulfate, dermatan sulfate or.
- Condroitin sulfate and hirudins their fragments, e.g. B. Hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 356), analogs or mutants, e.g. B. Hirulog® (WO 92/13952), coupled hirudins, e.g. B.
- hirudins e.g. B. PEG-hirudin
- the provision of a suitable antidote for coupled hirudins is particularly important.
- prothrombin factor II
- factor II has a high activity as an antidote for blood anticoagulants.
- the present invention therefore relates to a medicament containing prothrombin for antagonizing blood anticoagulants, these blood anticoagulants being able to be selected from the group comprising glycosaminoglycans and sulfated polysaccharides and hirudins, their fragments, analogs or mutants, natural and synthetic inhibitors of thromboplastin / Factor VIIa complex, factor Xa or thrombin, components of the protein C system, namely activated protein C, protein S, Thrombomodulin, fibrin aggregation or crosslinking inhibitors, substances from the vitamin K antagonist group, substances which influence platelet activation and / or aggregation or platelet adhesion, such as in particular fibrinogen receptor antagonists, or are able to increase the endogenous fibrinolysis capacity, such as in particular PAI-1 inhibitors or synthesis and secretion stimulators of plasminogen activator inhibitors.
- these blood anticoagulants being able to be selected from the group comprising glycosaminog
- prothrombin is also understood to mean active fragments or variants which can be produced conventionally or in particular by genetic engineering.
- Prothrombin is used in the medicament according to the invention in a concentration of 1 to 2000 international units (IU) per kilogram of body weight of the patient to be treated, concentrations of 10 to 1000 IU / kg being particularly preferred.
- IU international units
- the invention also relates to the use of prothrombin as an antidote for blood anticoagulants.
- the invention further relates to a method for producing a medicament which contains prothrombin for antagonizing blood anticoagulants.
- the present invention is further illustrated by the following example.
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Abstract
Description
Gegenstand der Erfindung ist ein Gegenmittel (Antidot) für Blut-Antikoagulanzien.The invention relates to an antidote for blood anticoagulants.
Die Blutgerinnung ist ein komplexer Prozeß, an dem Plasmaproteine und Zellen beteiligt sind. Die Bildung eines Wundverschlusses wird durch die rasche Adhäsion von Blutplättchen an die geschädigten Oberflächen und durch Proteasen und Kontaktfaktoren eingeleitet, die nacheinander in einer kaskadenartigen Reaktionsabfolge aktiviert werden. Am Ende dieser Vorgänge steht die Erzeugung von Thrombin, das unter anderem die Aktivierung von Fibrinogen zu Fibrin katalysiert.Blood clotting is a complex process involving plasma proteins and cells. The formation of a wound closure is initiated by the rapid adhesion of platelets to the damaged surfaces and by proteases and contact factors, which are activated in succession in a cascade-like reaction sequence. At the end of these processes is the production of thrombin, which among other things catalyzes the activation of fibrinogen to fibrin.
Proteine wie die Faktoren VIII und V tragen als Akzelleratoren zur Effizienz dieses Systems bei. Neben dem Protein C-System regulieren Inhibitoren der beteiligten Proteasen im wesentlichen die Gerinnungsprozesse dahingehend, daß ein Wundverschluß zustandekommt, jedoch überschießende Reaktionen vermieden werden. Wird dieses fein abgestimmte Gleichgewicht gestört, kann dies Fibrinablagerungen bzw. die Bildung von Thrombosen zur Folge haben. Bekanntermaßen sind resultierende Gefäßverschlüsse die Ursache für viele pathophysiologische Prozesse, wie insbesondere den Herzinfarkt. Diese Problematik bekommt ein besonderes Gewicht bei solchen Patienten, die einer erhöhten Thrombosegefahr ausgesetzt sind, was häufig eine postoperative Komplikation darstellt.Proteins such as factors VIII and V, as accelerators, contribute to the efficiency of this system. In addition to the protein C system, inhibitors of the proteases involved essentially regulate the coagulation processes in such a way that wound closure occurs, but excessive reactions are avoided. If this fine-tuned balance is disturbed, fibrin deposits or the formation of thromboses can result. As is known, resulting vascular occlusions are the cause of many pathophysiological processes, such as heart attacks in particular. This problem is particularly important in those patients who are at increased risk of thrombosis, which is often a postoperative complication.
Zur Verhinderung dieser pathophysiologischen Prozesse werden verschiedene Wege beschritten. So werden zur Verhinderung der Thrombusbildung bzw. zur Unterstützung deren Auflösung (Thrombolyse) in der Klinik häufig Antikoagulanzien angewendet, die in unterschiedlicher Art und Weise in das Gerinnungsgeschehen eingreifen. Neben der Reduktion bzw. Verhinderung der Thrombozytenfunktionen (Aggregation, Adhäsion, Aktivierung, Synthese und Ausschüttung von Aktivierungsprodukten) werden Hemmstoffe von beteiligten Gerinnungsproteasen, insbesondere des Thromboplastin/Faktor VIIa-Komplexes, des Faktors Xa und insbesondere des Thrombins (Faktor IIa) untersucht und angewendet.Various methods are used to prevent these pathophysiological processes. In order to prevent thrombus formation or to support its dissolution (thrombolysis), anticoagulants are often used in the clinic, which affect the coagulation process in different ways intervention. In addition to the reduction or prevention of platelet functions (aggregation, adhesion, activation, synthesis and release of activation products), inhibitors of coagulation proteases involved, in particular the thromboplastin / factor VIIa complex, factor Xa and in particular thrombin (factor IIa) are examined and applied .
Ein besonders spezifischer und potenter Inhibitor des Thrombins ist das Hirudin, das ursprünglich aus den Speicheldrüsen des Blutegels Hirudo medicinalis isoliert wurde. Mittlerweile sind verschiedene Varianten, Analoga, Fragmente und Mutanten davon bekannt und werden auf ihre Tauglichkeit untersucht. In seiner natürlich vorkommenden Form ist das Hirudin sulfatiert, jedoch wurde festgestellt, daß die interessante biologische Aktivität auch bei der nicht sulfatierten Form erhalten bleibt. Daher kann das Hirudin bzw. die Hirudin-Derivate in bequemer Weise mit den Mitteln der Gentechnologie hergestellt werden.A particularly specific and potent inhibitor of thrombin is hirudin, which was originally isolated from the salivary glands of the leech Hirudo medicinalis. Various variants, analogs, fragments and mutants thereof are now known and are being examined for their suitability. In its naturally occurring form, the hirudin is sulfated, but it has been found that the interesting biological activity is retained even in the non-sulfated form. The hirudin or the hirudin derivatives can therefore be conveniently produced using the means of genetic engineering.
Zu den Blut-Antikoagulanzien zählt auch das Heparin, dessen Fragmente und Varianten sowie synthetische Hemmstoffe, die die katalytische Aktivität des Thrombins und anderer Gerinnungsproteasen, z.B. Faktor Xa, inhibieren. Auch diese Komponenten können bei der Prophylaxe und/oder Therapie von thrombotischen bzw. präthrombotischen Komplikationen eingesetzt werden. Die Suche nach spezifischeren und potenteren Antikoagulanzien bzw. Antithrombotika reflektiert die unbefriedigende Situation, daß die klinisch etablierten Substanzen wie Heparine oder Vitamin K-Antagonisten entweder nicht effektiv genug sind oder, daß sie unerwünschte und zum Teil gravierende Nebenwirkungen aufweisen. Hirudin ist der stärkste derzeit bekannte Thrombininhibitor, der auch nicht in die anderen Enzyme der Blutgerinnungskaskade eingreift. Bisher wurden keine wesentlichen Nebeneinflüsse auf die Herzschlagrate, die Atmung, den Blutdruck, die Anzahl der Thrombozyten, den Fibrinogen- oder Hämoglobingehalt beobachtet. Daher handelt es sich bei Hirudin um ein bevorzugtes Blut-Antikoagulationsmittel.Blood anticoagulants also include heparin, its fragments and variants, and synthetic inhibitors that inhibit the catalytic activity of thrombin and other coagulation proteases, such as factor Xa. These components can also be used in the prophylaxis and / or therapy of thrombotic or prethrombotic complications. The search for more specific and potent anticoagulants or antithrombotics reflects the unsatisfactory situation that the clinically established substances such as heparins or vitamin K antagonists are either not effective enough or that they have undesirable and sometimes serious side effects. Hirudin is the strongest thrombin inhibitor currently known and does not interfere with the other enzymes in the blood coagulation cascade. So far, no significant side effects on the heart rate, respiration, blood pressure, the number of platelets, the fibrinogen or hemoglobin content have been observed. Therefore, hirudin is a preferred blood anticoagulant.
Die Anwendung von Antikoagulanzien bzw. Antithrombotika am Patienten bringt naturgemäß das Risiko einer erhöhten Blutungsneigung mit sich, die in extremen Situationen, z.B. bei unsachgemäßer Anwendung bzw. Dosierung zu unkontrollierten Blutungen führen kann. Um in einer derartigen Situation der unerwünschten Blutungsneigung gegensteuern zu können, ist es bei einigen Substanzen, deren Beschaffenheit (Molekulargewicht, Struktur) es erlaubt, möglich, diese schnell durch Dialyse aus dem Blutplasma des Patienten zu entfernen. Wenn dies aber aufgrund der apparativen Ausstattung oder aus sonstigen Gründen nicht möglich ist, muß ein Gegenmittel, das auch als Antidot bezeichnet wird, zur Verfügung gestellt werden.The use of anticoagulants or antithrombotics on the patient naturally entails the risk of an increased tendency to bleed, which occurs in extreme situations, e.g. improper use or dosage can lead to uncontrolled bleeding. In order to be able to counteract the undesirable tendency to bleed in such a situation, it is possible for some substances, the nature (molecular weight, structure) of which allows dialysis to be rapidly removed from the patient's blood plasma. However, if this is not possible due to the equipment or for other reasons, an antidote, also known as an antidote, must be made available.
Als Gegenmittel sind bereits einige Substanzen bzw. Präparate vorgeschlagen worden. So zeigen die Thrombine und deren blockierte Varianten einen gewissen Hirudin-neutralisierenden Effekt, jedoch ist einerseits die Anwendung von aktivem Thrombin bei Patienten, die mit Blut-Antikoagulanzien behandelt werden, in der Regel kontra-indiziert und andererseits ist die Präparation von inaktivem Thrombin durch Anwendung niedermolekularer, kovalente Bindungen eingehende Inhibitoren aufgrund der Toxizität dieser Substanzen problematisch. Außerdem fehlen auch Erfahrungen, ob diese Komplexe eine möglicherweise antigene Wirkung besitzen. Diese Komplexe sind auch aufgrund ihrer Natur nicht geeignet, niedermolekulare (synthetische) Antithrombine bzw. Antithrombotika zu neutralisieren. Das Meizothrombin, ein Intermediärprodukt, das bei der Aktivierung vom Prothrombin zu Thrombin kurzfristig entsteht, besitzt zwar eine gewisse Potenz zur Antagonisierung, jedoch kann es sich in vivo schnell zu Thrombin umwandeln und ist als solches in der Regel kontraindiziert.Some substances or preparations have already been proposed as antidotes. The thrombins and their blocked variants show a certain hirudin-neutralizing effect, but on the one hand the use of active thrombin in patients who are treated with blood anticoagulants is usually contraindicated and on the other hand the preparation of inactive thrombin by application Low molecular weight, covalent bonds inhibitors due to the toxicity of these substances problematic. There is also no experience as to whether these complexes may have an antigenic effect. Because of their nature, these complexes are not suitable for neutralizing low-molecular (synthetic) antithrombines or antithrombotics. Meizothrombin, an intermediate product that arises during activation from prothrombin to thrombin, has a certain potency to antagonize, but it can quickly convert to thrombin in vivo and as such is usually contraindicated.
Die Untersuchung des Faktor VII als Hirudin-Antidot in entsprechenden Modellen erbrachte keine befriedigenden Ergebnisse. In der europäischen Patentanmeldung EP A 89.810733.9 wird die Verwendung von Faktor VIII oder Fragmenten des Faktors VIII als Gegenmittel für Blut-Antikoagulanzien beschrieben. Bekannt ist auch, daß solche Substanzen verwendet werden können, die die Konzentration an Faktor VIII im Blut erhöhen, wie beispielsweise das Desmopressin (Mannucci, P.M.; Progress in Haemostasis and Thrombosis, 8 (1986), S. 19-45).The examination of factor VII as a hirudin antidote in corresponding models did not produce any satisfactory results. European patent application EP A 89.810733.9 describes the use of factor VIII or fragments of factor VIII as an antidote for blood anticoagulants. It is also known that substances which increase the concentration of factor VIII in the blood can be used, such as, for example, desmopressin (Mannucci, PM; Progress in Haemostasis and Thrombosis, 8 (1986), pp. 19-45).
Da aber auch diese Gegenmittel nicht für alle Anwendungsbereiche ausreichen, besteht nach wie vor die Notwendigkeit, effektivere und an Nebenwirkungen ärmere Gegenmittel für Blut-Antikoagulanzien, Antithrombotika bzw. Plättchenantagonisten bereitzustellen.However, since these antidotes are not sufficient for all areas of application, there is still a need to provide more effective antidotes for blood anticoagulants, antithrombotics or platelet antagonists with fewer side effects.
Unter antikoagulatorischen bzw. antithrombotischen Substanzen werden im Rahmen der vorliegenden Anmeldung Glykosaminoglykane und sulfatierte Polysaccharide, darunter Heparine, im besonderen unfraktioniertes und niedermolekulares (LMW-) Pentosanpolysulfat, Heparansulfat, Dermatansulfat oder. Condroitinsulfat sowie Hirudine, deren Fragmente, z. B. Hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 356), Analoga oder Mutanten, z. B. Hirulog® (WO 92/13952), gekoppelte Hirudine, z. B. PEG-Hirudin oder Hirutonine natürliche oder synthetische Inhibitoren des Thromboplastin/Faktor VIIaKomplexes, des Faktors Xa oder des Thrombins, Komponenten des Protein C-Systems, nämlich aktiviertes Protein C, Protein S, Thrombomodulin, Fibrinaggregations- oder Vernetzungshemmstoffe, Substanzen aus der Vitamin K-Antagonistengruppe, Substanzen, die die Plättchenaktivierung und/oder -aggregation bzw. Plättchenadhäsion beeinflussen, wie insbesondere Fibrinogenrezeptor-Antagonisten, oder die endogene Fibrinolysekapazität zu steigern vermögen, wie insbesondere PAI-1 Inhibitoren oder Synthese- und Sekretionsstimulatoren von Plasminogenaktivator-Inhibitoren und somit indirekt antithrombotisch wirken, verstanden.In the context of the present application, anticoagulant or antithrombotic substances include glycosaminoglycans and sulfated polysaccharides, including heparins, in particular unfractionated and low molecular weight (LMW) pentosan polysulfate, heparan sulfate, dermatan sulfate or. Condroitin sulfate and hirudins, their fragments, e.g. B. Hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 356), analogs or mutants, e.g. B. Hirulog® (WO 92/13952), coupled hirudins, e.g. B. PEG-hirudin or hirutonins natural or synthetic inhibitors of thromboplastin / factor VIIa complex, factor Xa or thrombin, components of the protein C system, namely activated protein C, protein S, thrombomodulin, fibrin aggregation or cross-linking inhibitors, substances from the vitamin K antagonist group, substances which influence platelet activation and / or aggregation or platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase endogenous fibrinolysis capacity, such as, in particular, PAI-1 inhibitors or synthesis and secretion stimulators of plasminogen activator inhibitors and thus act indirectly antithrombotic, understood.
Da die genannten gekoppelten Hirudine, z. B. PEG-Hirudin, aus dem Organismus nur schwer entfernbar sind, ist die Bereitstellung eines geeigneten Antidots für gekoppelte Hirudine besonders wichtig.Since the above-mentioned hirudins, e.g. B. PEG-hirudin, from which the organism is difficult to remove, the provision of a suitable antidote for coupled hirudins is particularly important.
Überraschenderweise wurde gefunden, daß Prothrombin (Faktor II) hohe Wirksamkeit als Gegenmittel für Blut-Antikoagulanzien besitzt.Surprisingly, it was found that prothrombin (factor II) has a high activity as an antidote for blood anticoagulants.
Gegenstand der vorliegenden Erfindung ist deshalb ein Arzneimittel, enthaltend Prothrombin zur Antagonisierung von Blut-Antikoagulanzien, wobei diese Blut-Antikoagulanzien ausgewählt sein können aus der Gruppe umfassend Glykosaminoglykane und sulfatierte Polysaccharide sowie Hirudine, deren Fragmente, Analoga oder Mutanten, natürliche und synthetische Inhibitoren des Thromboplastins/Faktor VIIa-Komplexes, des Faktors Xa oder des Thrombins, Komponenten des Protein C-Systems, nämlich aktiviertes Protein C, Protein S, Thrombomodulin, Fibrinaggregations- oder Vernetzungshemmstoffe, Substanzen aus der Vitamin K-Antagonistengruppe, Substanzen, die die Plättchenaktivierung und/oder -aggregation bzw. Plättchenadhäsion beeinflussen, wie insbesondere Fibrinogenrezeptor-Antagonisten, oder die endogene Fibrinolysekapazität zu steigern vermögen, wie insbesondere PAI-1 Inhibitoren oder Synthese- und Sekretionsstimulatoren von Plasminogenaktivator-Inhibitoren.The present invention therefore relates to a medicament containing prothrombin for antagonizing blood anticoagulants, these blood anticoagulants being able to be selected from the group comprising glycosaminoglycans and sulfated polysaccharides and hirudins, their fragments, analogs or mutants, natural and synthetic inhibitors of thromboplastin / Factor VIIa complex, factor Xa or thrombin, components of the protein C system, namely activated protein C, protein S, Thrombomodulin, fibrin aggregation or crosslinking inhibitors, substances from the vitamin K antagonist group, substances which influence platelet activation and / or aggregation or platelet adhesion, such as in particular fibrinogen receptor antagonists, or are able to increase the endogenous fibrinolysis capacity, such as in particular PAI-1 inhibitors or synthesis and secretion stimulators of plasminogen activator inhibitors.
Unter Prothrombin werden im Rahmen vorliegender Erfindung auch aktive Fragmente oder Varianten verstanden, die konventionell oder insbesondere gentechnologisch hergestellt werden können.In the context of the present invention, prothrombin is also understood to mean active fragments or variants which can be produced conventionally or in particular by genetic engineering.
In dem erfindungsgemäßen Arzneimittel wird Prothrombin in einer Konzentration von 1 bis 2000 Internationalen Einheiten (IU) pro Kilogramm Körpergewicht des zu behandelnden Patienten eingesetzt, wobei Konzentrationen von 10 bis 1000 IU/kg besonders bevorzugt sind.Prothrombin is used in the medicament according to the invention in a concentration of 1 to 2000 international units (IU) per kilogram of body weight of the patient to be treated, concentrations of 10 to 1000 IU / kg being particularly preferred.
Die Erfindung betrifft auch die Verwendung von Prothrombin als Gegenmittel für Blut-Antikoagulanzien.The invention also relates to the use of prothrombin as an antidote for blood anticoagulants.
Weiterhin betrifft die Erfindung ein Verfahren zur Herstellung eines Arzneimittels, welches Prothrombin enthält zur Antagonisierung von Blut-Antikoagulanzien.The invention further relates to a method for producing a medicament which contains prothrombin for antagonizing blood anticoagulants.
Die vorliegende Erfindung wird durch das nachfolgende Beispiel weiter erläutert.The present invention is further illustrated by the following example.
Standard-Humanplasma (SHP), das mit 20 µg/ml Hirudin versetzt wurde, wurde in der aPTT auf antagonisierende Wirkung durch Prothrombin (F II) untersucht. Die in der Tabelle demonstrierten Gerinnungszeiten belegen die Wirksamkeit des Prothrombins.
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4430204 | 1994-08-26 | ||
| DE4430204A DE4430204A1 (en) | 1994-08-26 | 1994-08-26 | Medicament, which is suitable as an antidote for blood anticoagulants and its use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0700682A2 true EP0700682A2 (en) | 1996-03-13 |
| EP0700682A3 EP0700682A3 (en) | 1996-05-29 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP95112569A Withdrawn EP0700682A3 (en) | 1994-08-26 | 1995-08-10 | Medicament containing prothrombin for antagonizing blood-anticoagulents |
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| Country | Link |
|---|---|
| EP (1) | EP0700682A3 (en) |
| JP (1) | JP3838680B2 (en) |
| KR (1) | KR960006920A (en) |
| AU (1) | AU708409B2 (en) |
| CA (1) | CA2156990A1 (en) |
| DE (1) | DE4430204A1 (en) |
| IL (1) | IL115057A0 (en) |
| ZA (1) | ZA957140B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003099324A1 (en) * | 2002-05-23 | 2003-12-04 | Chugai Seiyaku Kabushiki Kaisha | Agent neutralizint tissue factor inhibitor and agent neutralizing activated blood coagulation factor viii preparation |
| US7842477B2 (en) | 2003-10-14 | 2010-11-30 | Astrazeneca Ab | Methods for producing gamma-carboxylated proteins |
| US7989193B2 (en) | 2005-04-13 | 2011-08-02 | Medimmune Limited | Compositions and methods for producing gamma-carboxylated proteins |
| US8206967B2 (en) | 2007-07-06 | 2012-06-26 | Medimmune Limited | Method for production of recombinant human thrombin |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19625642A1 (en) * | 1996-06-26 | 1998-01-08 | Max Planck Gesellschaft | A process for preparing an antidote precursor for natural and synthetic thrombin inhibitors |
| KR20030031380A (en) * | 2001-10-13 | 2003-04-21 | 이우진 | Skateboard |
| KR20040046045A (en) * | 2002-11-26 | 2004-06-05 | 김재영 | Paduk board and chess board that use copper material and maunfacturing method thereof |
| CN103221061A (en) * | 2010-10-06 | 2013-07-24 | 米迪缪尼有限公司 | Factor II and fibrinogen for treatment of haemostatic disorders |
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| EP0333356A2 (en) | 1988-03-04 | 1989-09-20 | Biogen, Inc. | Hirudin peptides |
| WO1992013952A1 (en) | 1991-02-08 | 1992-08-20 | Biogen, Inc. | Improved inhibitors of thrombin |
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| JPS5850202B2 (en) * | 1977-11-10 | 1983-11-09 | 第一製薬株式会社 | Production method of prothrompin |
| DE3043857A1 (en) * | 1980-11-21 | 1982-07-08 | Behringwerke Ag, 3550 Marburg | METHOD FOR THE PRODUCTION OF BLOOD coagulation FACTORS AND THE PREPARATION OF FACTORS II AND VII THEREFORE PRODUCED |
| DD251078A1 (en) * | 1986-07-17 | 1987-11-04 | Bezirksinstitut Fuer Blutspend | PROCESS FOR THE PREPARATION OF PROTHROMBIN CONCENTRATES |
| GB8729822D0 (en) * | 1987-12-22 | 1988-02-03 | Central Blood Lab Authority | Chemical process |
| JPH0219400A (en) * | 1988-07-07 | 1990-01-23 | Green Cross Corp:The | Production of thrombin or prothronbin |
| WO1991011519A1 (en) * | 1990-01-26 | 1991-08-08 | Immuno Aktiengesellschaft | Recombinantly produced blood factors and process for the expression of said blood factors, as well as vaccinia virus recombinants used in said process |
| DE4203965A1 (en) * | 1992-02-11 | 1993-08-12 | Max Planck Gesellschaft | ANTIDOT FOR HIRUDIN AND SYNTHETIC THROMBIN INHIBITORS |
| AT397391B (en) * | 1992-05-15 | 1994-03-25 | Immuno Ag | USE OF PROTHROMIN FRAGMENTS |
-
1994
- 1994-08-26 DE DE4430204A patent/DE4430204A1/en not_active Withdrawn
-
1995
- 1995-08-10 EP EP95112569A patent/EP0700682A3/en not_active Withdrawn
- 1995-08-24 AU AU30256/95A patent/AU708409B2/en not_active Ceased
- 1995-08-24 IL IL11505795A patent/IL115057A0/en unknown
- 1995-08-25 KR KR1019950026511A patent/KR960006920A/en not_active Application Discontinuation
- 1995-08-25 ZA ZA957140A patent/ZA957140B/en unknown
- 1995-08-25 CA CA002156990A patent/CA2156990A1/en not_active Abandoned
- 1995-08-25 JP JP21683995A patent/JP3838680B2/en not_active Expired - Fee Related
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| EP0333356A2 (en) | 1988-03-04 | 1989-09-20 | Biogen, Inc. | Hirudin peptides |
| WO1992013952A1 (en) | 1991-02-08 | 1992-08-20 | Biogen, Inc. | Improved inhibitors of thrombin |
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| C.V.PROWSE, J.D.CASH: "The use of Factor IX Concentrates in Man: a 9-Year Experience of Scottish Concentrates in the South-East of Scotland", BRITISH JOURNAL OF HAEMATOLOGY, no. 47, 1981, EDINBURGH, pages 91 - 104 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003099324A1 (en) * | 2002-05-23 | 2003-12-04 | Chugai Seiyaku Kabushiki Kaisha | Agent neutralizint tissue factor inhibitor and agent neutralizing activated blood coagulation factor viii preparation |
| US7842477B2 (en) | 2003-10-14 | 2010-11-30 | Astrazeneca Ab | Methods for producing gamma-carboxylated proteins |
| US8697440B2 (en) | 2003-10-14 | 2014-04-15 | Medimmune Limited | Compositions and methods for producing gamma-carboxylated proteins |
| US7989193B2 (en) | 2005-04-13 | 2011-08-02 | Medimmune Limited | Compositions and methods for producing gamma-carboxylated proteins |
| US8304224B2 (en) | 2005-04-13 | 2012-11-06 | Medimmune Limited | Compositions and methods relating to proteins requiring gamma-carboxylation |
| US8206967B2 (en) | 2007-07-06 | 2012-06-26 | Medimmune Limited | Method for production of recombinant human thrombin |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0859505A (en) | 1996-03-05 |
| AU3025695A (en) | 1996-03-07 |
| EP0700682A3 (en) | 1996-05-29 |
| AU708409B2 (en) | 1999-08-05 |
| JP3838680B2 (en) | 2006-10-25 |
| IL115057A0 (en) | 1995-12-08 |
| ZA957140B (en) | 1996-03-26 |
| DE4430204A1 (en) | 1996-02-29 |
| KR960006920A (en) | 1996-03-22 |
| CA2156990A1 (en) | 1996-02-27 |
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